There is an urgent need for novel therapies to treat glioblastomas (GBMs), the most common and aggressive primary tumor of the nervous system. Patients diagnosed with these brain tumors typically die within a year and there is no effective treatment available. The laboratory of Dr. Nephi Stella recently discovered a new subclass of indole compounds that activates GPR124, a GPCR with established relevance in tumor pathogenesis. These indoles demonstrate efficacy in both in vitro and in vivo models of GBMs. Notably, no overt toxicity was observed in mice dosed over a three week period. The goal of Stella Therapeutics, a newly formed start-up company, is to develop drugs that target GPR124 and exhibit therapeutic value. Thus, in this proof-of-concept work, they will: Aim 1: Validate an i vitro assay that measures agonist activity at GPR124, format this assay for HTS, and screen two compound libraries. Aim 2: Prioritize hits and perform secondary screens. By the end of this SBIR phase I, Stella Therapeutics will have selected compounds (preferably with more than one scaffold) that are agonists at GPR124, kill GBMs and do not harm healthy cells. Their phase II SBIR will further develop the anti-tumor efficacy of these selected compounds by performing focused medicinal chemistry, testing therapeutic efficacy against state-of-the-art animal models of GBMs and systematically verifying toxicity in small and large animals. The overall goal of Stella Therapeutics is to develop drugs that target GPR124 and ready to treat human GBMs.